Jeffrey Hodgin - Academia.edu (original) (raw)
Papers by Jeffrey Hodgin
Proceedings of the National Academy of Sciences of the United States of America, Mar 28, 1995
Variants of the human angiotensinogen gene have been linked in some studies to increased circulat... more Variants of the human angiotensinogen gene have been linked in some studies to increased circulating angiotensinogen levels and essential hypertension. To test for direct causality between genotypes at the angiotensinogen locus and blood pressures, we have studied mice carrying zero, one, two, three, or four functional copies of the murine wild-type angiotensinogen gene (Agt) at its normal chromosomal location. Plasma angiotensinogen levels increase progressively, although not linearly, from zero in the zero-copy animals to 145% of normal in the four-copy animals. Mice of all genotypes are normal at birth, but most zero-copy animals die before weaning. The kidneys of the zero-copy animals show pathological changes as adults, but the kidneys are normal in the other genotypes. One adult zero-copy male tested was fertile. The blood pressures of the one-copy through four-copy animals show significant and almost linear increases of approximately 8 mmHg per gene copy despite their normal compensatory mechanisms being intact. These results establish a direct causal relationship between Agt genotypes and blood pressures.
Nature, May 1, 1995
Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasocons... more Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
Hypertension, May 1, 1995
We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mic... more We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mice. The system was designed to perform all functions automatically, including a programmable routine of cuff inflation and deflation, analysis and assignment of pulse rate and blood pressure, and recording of data electronically. To evaluate this system over a range of blood pressures, we gave groups of mice enalapril or N G -nitro- l -arginine methyl ester in their drinking water. For each of these groups, an equal number of control mice were given nothing in their drinking water. Tail-cuff blood pressures were recorded as the means of blood pressures determined on at least 3 days after at least 7 days of training. Tail-cuff enalapril and control group means were measured both 3 and 4 months after enalapril (or no drug) was begun; the group means at 3 months were not significantly different from the group means at 4 months. These results demonstrate that the system gives reproducible results. After the tail-cuff measurements were completed, intra-arterial blood pressures were attempted in all mice under unrestrained, unanesthetized conditions, and individual mouse (n=22) blood pressures with the use of the two methods were compared. The blood pressures from individual mice by tail-cuff and intra-arterial methods were highly correlated ( r =.86, P <.01). The means for the four mouse groups were also highly correlated ( r =.98, P <.02). These data show that blood pressures measured on trained mice by a computerized noninvasive tail-cuff system are reproducible and correlate well with intra-arterial blood pressures measured on unrestrained, unanesthetized mice.
Proceedings of the National Academy of Sciences, 1998
Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid ... more Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously generated and studied knockout mice lacking estrogen receptor α and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor β (ERβ −/−) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERβ −/− mice lack normal ERβ RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal ...
Hypertension, 1995
We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mic... more We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mice. The system was designed to perform all functions automatically, including a programmable routine of cuff inflation and deflation, analysis and assignment of pulse rate and blood pressure, and recording of data electronically. To evaluate this system over a range of blood pressures, we gave groups of mice enalapril or N G -nitro- l -arginine methyl ester in their drinking water. For each of these groups, an equal number of control mice were given nothing in their drinking water. Tail-cuff blood pressures were recorded as the means of blood pressures determined on at least 3 days after at least 7 days of training. Tail-cuff enalapril and control group means were measured both 3 and 4 months after enalapril (or no drug) was begun; the group means at 3 months were not significantly different from the group means at 4 months. These results demonstrate that the system gives reproducible res...
PloS one, 2016
The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 col... more The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's ...
Journal of the American Society of Nephrology : JASN, Jan 11, 2014
The attrition rate of functioning allografts beyond the first year has not improved despite impro... more The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed t...
Arthritis & Rheumatology, 2013
Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with o... more Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease resulting from activation of both innate and adaptive immune pathways. Recently, increased activation of the inflammasome machinery in SLE has been described. Using the mouse model of pristane-induced lupus, we undertook this study to explore whether caspase 1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction.
Nature, 1995
Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasocons... more Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
Journal of Clinical Investigation, 2001
The inhibitory effects of estrogen (17β-estradiol) on atherosclerosis have been well documented i... more The inhibitory effects of estrogen (17β-estradiol) on atherosclerosis have been well documented in numerous animal models, and epidemiological evidence supports this protective effect in humans. The detailed mechanisms for this protection are not understood, but most are thought to be mediated through estrogen receptors (ERs), of which two are known (ERα and ERβ). To investigate the role of ERα in the atheroprotective effect of 17β-estradiol (E2), we ovariectomized female mice that lack apoE (AAee) or lack both apoE and ERα (ααee), and treated half of them with E2 for three months. E2 treatment of ovariectomized AAee females dramatically reduced the size of the lesions as well as their histological complexity. Plasma cholesterol was significantly reduced in this group, although the observed extent of protection by E2 was greater than could be explained solely by the change in lipid levels. In contrast, E2 treatment of ovariectomized ααee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with ααee mice without E2, demonstrating that ERα is a major mediator of the atheroprotective effect of E2. Nevertheless, E2 treatment significantly reduced the complexity of plaques in the ααee females, although not to the same degree as in AAee females, suggesting the existence of ERα-independent atheroprotective effects of E2.
Journal of the American Society of Nephrology : JASN, Jan 2, 2015
Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasin... more Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) µm(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) µm(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (...
Endocrinology, 2002
The use of hormone replacement therapy for coronary heart disease prevention in humans has been a... more The use of hormone replacement therapy for coronary heart disease prevention in humans has been an area of intense controversy. The atheroprotective qualities of estrogens have been challenged recently by several negative results of randomized clinical trials in postmenopausal women. However, the inhibitory effects of estrogens on atherogenesis are well documented in numerous animals, including atherosclerotic mouse models, but the detailed mechanisms of this protection are not understood. In this minireview, we will focus on the considerable success that has been achieved in demonstrating the atheroprotective effects of 17beta-estradiol in apolipoprotein E and low-density lipoprotein receptor-deficient mice and the use of these atherosclerotic mouse models in pharmacological and genetic study designs to investigate antiatherogenic mechanisms of estrogens. Mouse models of atherosclerosis should prove beneficial to understanding the cellular and molecular mechanisms of estrogen-media...
Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing e... more Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing end-stage renal disease. These disorders may associate low level glomerular inflammation and podocyte expression of inflammatory mediators. However, the factors regulating podocyte expression of inflammatory mediators in vivo in non-immune disorders are poorly understood. We have now explored the regulation and role of TWEAK receptor Fn14 in mediating glomerular inflammation in cultured podocytes and in experimental and human non-immune proteinuria. Transcriptomics disclosed Fn14 and MCP-1 mRNA upregulation in glomeruli from patients with focal segmental glomerulosclerosis, as well as a correlation between the expression of both transcripts. Increased glomerular Fn14 and MCP-1 mRNA was confirmed in a second focal segmental glomerulosclerosis cohort and was also observed in membranous nephropathy. In human non-proliferative proteinuric kidney diseases podocytes displayed Fn14 and MCP-1 expression and NFκB activation. Podocyte Fn14 was increased in murine protein overload-induced proteinuria. In Fn14 knock-out mice with protein overload-induced proteinuria, glomerular and periglomerular macrophage infiltrates were reduced, as were MCP-1 mRNA and podocyte MCP-1 staining and podocyte numbers preserved as compared to wild-type counterparts. Adenovirus-mediated overexpression of TWEAK increased periglomerular macrophage infiltration in mice without prior kidney injury. In cultured podocytes inflammatory cytokines increased Fn14 mRNA and protein levels. TWEAK activated NFκB and increased MCP-1 mRNA and protein, an effect prevented by the NFκB inhibitor parthenolide. In conclusion, Fn14 activation results in NFκB-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immune origin.
Pediatric Nephrology, 2014
Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, ca... more Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, caused by failure of the glomerular filtration barrier, resulting in massive proteinuria. Our current diagnostic, prognostic and therapeutic decisions in NS are largely based upon clinical or histological patterns such as &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;focal segmental glomerulosclerosis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;steroid sensitive&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;. Yet these descriptive classifications lack the precision to explain the physiologic origins and clinical heterogeneity observed in this syndrome. A more precise definition of NS is required to identify mechanisms of disease and capture various clinical trajectories. An integrative genomics approach to NS applies bioinformatics and computational methods to comprehensive experimental, molecular and clinical data for holistic disease definition. A unique aspect is analysis of data together to discover NS-associated molecules, pathways, and networks. Integrating multidimensional datasets from the outset highlights how molecular lesions impact the entire individual. Data sets integrated range from genetic variation to gene expression, to histologic changes, to progression of chronic kidney disease (CKD). This review will introduce the tenets of integrative genomics and suggest how it can increase our understanding of NS from molecular and pathophysiological perspectives. A diverse group of genome-scale experiments are presented that have sought to define molecular signatures of NS. Finally, the Nephrotic Syndrome Study Network (NEPTUNE) will be introduced as an international, prospective cohort study of patients with NS that utilizes an integrated systems genomics approach from the outset. A major NEPTUNE goal is to achieve comprehensive disease definition from a genomics perspective and identify shared molecular drivers of disease.
PloS one, 2014
IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary pr... more IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. ...
Arthritis & Rheumatology, 2013
Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with o... more Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease resulting from activation of both innate and adaptive immune pathways. Recently, increased activation of the inflammasome machinery in SLE has been described. Using the mouse model of pristane-induced lupus, we undertook this study to explore whether caspase 1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction.
Journal of the American Society of Nephrology : JASN, Jan 11, 2014
The attrition rate of functioning allografts beyond the first year has not improved despite impro... more The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed t...
The Journal of Immunology, 2011
Proceedings of the National Academy of Sciences of the United States of America, Mar 28, 1995
Variants of the human angiotensinogen gene have been linked in some studies to increased circulat... more Variants of the human angiotensinogen gene have been linked in some studies to increased circulating angiotensinogen levels and essential hypertension. To test for direct causality between genotypes at the angiotensinogen locus and blood pressures, we have studied mice carrying zero, one, two, three, or four functional copies of the murine wild-type angiotensinogen gene (Agt) at its normal chromosomal location. Plasma angiotensinogen levels increase progressively, although not linearly, from zero in the zero-copy animals to 145% of normal in the four-copy animals. Mice of all genotypes are normal at birth, but most zero-copy animals die before weaning. The kidneys of the zero-copy animals show pathological changes as adults, but the kidneys are normal in the other genotypes. One adult zero-copy male tested was fertile. The blood pressures of the one-copy through four-copy animals show significant and almost linear increases of approximately 8 mmHg per gene copy despite their normal compensatory mechanisms being intact. These results establish a direct causal relationship between Agt genotypes and blood pressures.
Nature, May 1, 1995
Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasocons... more Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
Hypertension, May 1, 1995
We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mic... more We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mice. The system was designed to perform all functions automatically, including a programmable routine of cuff inflation and deflation, analysis and assignment of pulse rate and blood pressure, and recording of data electronically. To evaluate this system over a range of blood pressures, we gave groups of mice enalapril or N G -nitro- l -arginine methyl ester in their drinking water. For each of these groups, an equal number of control mice were given nothing in their drinking water. Tail-cuff blood pressures were recorded as the means of blood pressures determined on at least 3 days after at least 7 days of training. Tail-cuff enalapril and control group means were measured both 3 and 4 months after enalapril (or no drug) was begun; the group means at 3 months were not significantly different from the group means at 4 months. These results demonstrate that the system gives reproducible results. After the tail-cuff measurements were completed, intra-arterial blood pressures were attempted in all mice under unrestrained, unanesthetized conditions, and individual mouse (n=22) blood pressures with the use of the two methods were compared. The blood pressures from individual mice by tail-cuff and intra-arterial methods were highly correlated ( r =.86, P <.01). The means for the four mouse groups were also highly correlated ( r =.98, P <.02). These data show that blood pressures measured on trained mice by a computerized noninvasive tail-cuff system are reproducible and correlate well with intra-arterial blood pressures measured on unrestrained, unanesthetized mice.
Proceedings of the National Academy of Sciences, 1998
Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid ... more Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously generated and studied knockout mice lacking estrogen receptor α and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor β (ERβ −/−) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERβ −/− mice lack normal ERβ RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal ...
Hypertension, 1995
We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mic... more We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mice. The system was designed to perform all functions automatically, including a programmable routine of cuff inflation and deflation, analysis and assignment of pulse rate and blood pressure, and recording of data electronically. To evaluate this system over a range of blood pressures, we gave groups of mice enalapril or N G -nitro- l -arginine methyl ester in their drinking water. For each of these groups, an equal number of control mice were given nothing in their drinking water. Tail-cuff blood pressures were recorded as the means of blood pressures determined on at least 3 days after at least 7 days of training. Tail-cuff enalapril and control group means were measured both 3 and 4 months after enalapril (or no drug) was begun; the group means at 3 months were not significantly different from the group means at 4 months. These results demonstrate that the system gives reproducible res...
PloS one, 2016
The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 col... more The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's ...
Journal of the American Society of Nephrology : JASN, Jan 11, 2014
The attrition rate of functioning allografts beyond the first year has not improved despite impro... more The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed t...
Arthritis & Rheumatology, 2013
Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with o... more Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease resulting from activation of both innate and adaptive immune pathways. Recently, increased activation of the inflammasome machinery in SLE has been described. Using the mouse model of pristane-induced lupus, we undertook this study to explore whether caspase 1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction.
Nature, 1995
Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasocons... more Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
Journal of Clinical Investigation, 2001
The inhibitory effects of estrogen (17β-estradiol) on atherosclerosis have been well documented i... more The inhibitory effects of estrogen (17β-estradiol) on atherosclerosis have been well documented in numerous animal models, and epidemiological evidence supports this protective effect in humans. The detailed mechanisms for this protection are not understood, but most are thought to be mediated through estrogen receptors (ERs), of which two are known (ERα and ERβ). To investigate the role of ERα in the atheroprotective effect of 17β-estradiol (E2), we ovariectomized female mice that lack apoE (AAee) or lack both apoE and ERα (ααee), and treated half of them with E2 for three months. E2 treatment of ovariectomized AAee females dramatically reduced the size of the lesions as well as their histological complexity. Plasma cholesterol was significantly reduced in this group, although the observed extent of protection by E2 was greater than could be explained solely by the change in lipid levels. In contrast, E2 treatment of ovariectomized ααee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with ααee mice without E2, demonstrating that ERα is a major mediator of the atheroprotective effect of E2. Nevertheless, E2 treatment significantly reduced the complexity of plaques in the ααee females, although not to the same degree as in AAee females, suggesting the existence of ERα-independent atheroprotective effects of E2.
Journal of the American Society of Nephrology : JASN, Jan 2, 2015
Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasin... more Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) µm(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) µm(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (...
Endocrinology, 2002
The use of hormone replacement therapy for coronary heart disease prevention in humans has been a... more The use of hormone replacement therapy for coronary heart disease prevention in humans has been an area of intense controversy. The atheroprotective qualities of estrogens have been challenged recently by several negative results of randomized clinical trials in postmenopausal women. However, the inhibitory effects of estrogens on atherogenesis are well documented in numerous animals, including atherosclerotic mouse models, but the detailed mechanisms of this protection are not understood. In this minireview, we will focus on the considerable success that has been achieved in demonstrating the atheroprotective effects of 17beta-estradiol in apolipoprotein E and low-density lipoprotein receptor-deficient mice and the use of these atherosclerotic mouse models in pharmacological and genetic study designs to investigate antiatherogenic mechanisms of estrogens. Mouse models of atherosclerosis should prove beneficial to understanding the cellular and molecular mechanisms of estrogen-media...
Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing e... more Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing end-stage renal disease. These disorders may associate low level glomerular inflammation and podocyte expression of inflammatory mediators. However, the factors regulating podocyte expression of inflammatory mediators in vivo in non-immune disorders are poorly understood. We have now explored the regulation and role of TWEAK receptor Fn14 in mediating glomerular inflammation in cultured podocytes and in experimental and human non-immune proteinuria. Transcriptomics disclosed Fn14 and MCP-1 mRNA upregulation in glomeruli from patients with focal segmental glomerulosclerosis, as well as a correlation between the expression of both transcripts. Increased glomerular Fn14 and MCP-1 mRNA was confirmed in a second focal segmental glomerulosclerosis cohort and was also observed in membranous nephropathy. In human non-proliferative proteinuric kidney diseases podocytes displayed Fn14 and MCP-1 expression and NFκB activation. Podocyte Fn14 was increased in murine protein overload-induced proteinuria. In Fn14 knock-out mice with protein overload-induced proteinuria, glomerular and periglomerular macrophage infiltrates were reduced, as were MCP-1 mRNA and podocyte MCP-1 staining and podocyte numbers preserved as compared to wild-type counterparts. Adenovirus-mediated overexpression of TWEAK increased periglomerular macrophage infiltration in mice without prior kidney injury. In cultured podocytes inflammatory cytokines increased Fn14 mRNA and protein levels. TWEAK activated NFκB and increased MCP-1 mRNA and protein, an effect prevented by the NFκB inhibitor parthenolide. In conclusion, Fn14 activation results in NFκB-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immune origin.
Pediatric Nephrology, 2014
Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, ca... more Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, caused by failure of the glomerular filtration barrier, resulting in massive proteinuria. Our current diagnostic, prognostic and therapeutic decisions in NS are largely based upon clinical or histological patterns such as &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;focal segmental glomerulosclerosis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;steroid sensitive&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;. Yet these descriptive classifications lack the precision to explain the physiologic origins and clinical heterogeneity observed in this syndrome. A more precise definition of NS is required to identify mechanisms of disease and capture various clinical trajectories. An integrative genomics approach to NS applies bioinformatics and computational methods to comprehensive experimental, molecular and clinical data for holistic disease definition. A unique aspect is analysis of data together to discover NS-associated molecules, pathways, and networks. Integrating multidimensional datasets from the outset highlights how molecular lesions impact the entire individual. Data sets integrated range from genetic variation to gene expression, to histologic changes, to progression of chronic kidney disease (CKD). This review will introduce the tenets of integrative genomics and suggest how it can increase our understanding of NS from molecular and pathophysiological perspectives. A diverse group of genome-scale experiments are presented that have sought to define molecular signatures of NS. Finally, the Nephrotic Syndrome Study Network (NEPTUNE) will be introduced as an international, prospective cohort study of patients with NS that utilizes an integrated systems genomics approach from the outset. A major NEPTUNE goal is to achieve comprehensive disease definition from a genomics perspective and identify shared molecular drivers of disease.
PloS one, 2014
IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary pr... more IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. ...
Arthritis & Rheumatology, 2013
Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with o... more Objective. Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease resulting from activation of both innate and adaptive immune pathways. Recently, increased activation of the inflammasome machinery in SLE has been described. Using the mouse model of pristane-induced lupus, we undertook this study to explore whether caspase 1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction.
Journal of the American Society of Nephrology : JASN, Jan 11, 2014
The attrition rate of functioning allografts beyond the first year has not improved despite impro... more The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed t...
The Journal of Immunology, 2011